**7. Results**

In the open population among men aged 25–64 years, the frequency of 4/4 homozygous genotype of the D4 subtype of the dopamine receptor (DRD4) was 57.9%, 2/2 genotype was found to be less frequent - 6.1%, 2/4 genotype - 12, 5% and 3/4 genotype - 5.6%; even less frequent: 4/6 genotype - 4.2%, 2/6 genotype, 4/7 and 6/6 genotypes were found in the identical proportions of 2.1%. The frequency distribution of alleles showed that the 4 allele predominates - 70.7%, the 2 allele was found at 14%, the 6 allele was at 6%. The other alleles make up 0.8% - 5.4% (**Table 1**).

The distribution of carriers of VNTR genotypes of DRD4 gene polymorphism by anxiety level is presented in **Table 1**. Associative analysis revealed that carriers of the DRD4 genotype 4/4 are much more likely to be found in the group with moderate anxiety (59.8%) and mild anxiety (66.7%) than in the group with severe anxiety (54.8%). Carriers of the 2/4 genotype were much more frequent in the group with moderate anxiety (14.5%) than with severe anxiety where the level was 9.6% (χ2 = 69.569 υ = 36 p = 0.001). On the contrary, carriers of the 4/6 genotype were more frequently found in the group with a severe level of anxiety - 7.8%, versus with a moderate level of anxiety - 2%. Moreover, the occurrence of carriers of the 4/6 genotype in the group with severe anxiety was more frequent than in the group with moderate anxiety, in comparison with carriers of all other genotypes OR = 4.2 (95% CI 1.4–12.1); (χ2 = 8.521 υ = 1 p < 0.01), 2/2 genotype (χ2 = 7.326 υ = 1 p = 0.007), 2/4 genotype (χ2 = 9.825 υ = 1 p = 0.002), 4/4 genotype (χ2 = 8.543 υ = 1 p = 0.003). The similar situation can be seen in groups of anxiety and carriage of alleles 2, 3, 4 and 6. Carriers of alleles 2 and 4 prevailed in the group with moderate anxiety - 15.6% and 72.1%, respectively, whereas, in the group with severe anxiety they were represented - 11.7% and 68.7%, respectively (χ2 = 15.980 υ = 12 p > 0.05). Carriers of allele 3 in the group with severe anxiety were found in 7.5%, and with moderate anxiety −3.9%, with severe anxiety found in them 2 times (95% CI 1–3.6) more often than carriers of all other alleles (χ2 = 5240 υ = 1 p = 0,022), carriers of allele 2 (χ2 = 7122 υ = 1 p < 0,01) and allele 4 OR = 2 (95% CI 1–3,7); (χ2 = 5.284 υ = 1 p < 0.05). Similarly, carriers of the allele 6 in the group with severe anxiety were found in 7.8%, and in the group with moderate anxiety - 4.7%, and the frequency of severe levels of anxiety was higher than in the carriers of all other alleles OR = 1, 7 (95% CI 0.9–3; χ2 = 3.5 υ = 1, p < 0.05), carriers of allele 2 (χ2 = 5.499 υ = 1 p < 0.01), carriers of allele 4 (χ2 = 3689 υ = 1 p < 0,05).



**Table 1.** *Frequencies of VNTR genotypes and alleles of DRD4 gene polymorphism in a population and their association with psychosocial factors.*

#### *Association of Personal Anxiety with Dopamine Receptor D4 (DRD4), DAT Genes Polymorphism DOI: http://dx.doi.org/10.5772/intechopen.94386*

The distribution of carriers of VNTR genotypes of DRD4 gene polymorphism by depression level is shown in **Table 1**. Carriers of the DRD4 genotype 4/4 and 2/4 were most frequently found in the group where there was no depression (60.5% and 14.5%, respectively) than in the group with depression (51.9% and 7.8%, respectively) (χ2 = 32.811 υ = 18 p < 0.05). In contrast, carriers of the 4/6 genotype were more likely to be found in the group with depression (9.3%) than in the group without depression (2%), and compared with carriers of all other genotypes, OR = 4.9 (95% CI 1.8–13.5); (χ2 = 11.725 υ = 1 p < 0.001), carriers of the 2/2 genotype (χ2 = 6.848 υ = 1 p < 0.01), 2/4 genotype (χ2 = 14.356 υ = 1 p < 0.0001), 3/4 genotype (χ2 = 4582 υ = 1 p < 0,05) and 4/4 genotype (χ2 = 12,436 υ = 1 p = 0,00001). Carriers of 6/6 homozygous genotype were also more frequently found in the group with depression (3.9%) than without depression (0.3), compared with carriers of the 2/4 genotype (without depression −14.5%, with depression −7, 8%) (χ2 = 5645 υ = 1 p = 0,017). The similar situation can be seen in the groups with and without depression in the carriage of long and short alleles of the DRD4 gene (**Table 1**). Carriers of allele 2 and 4 are more frequent in the group without depression (15% and 72.8%, respectively) than in the group with depression (11.6% and 65.9%, respectively) (χ2 = 24.678 υ = 6 p < 0.00001). Carriers of the long allele 6, on the contrary, are more frequently found in the group with depression (11.2%) than in the group without depression (3.7%), and compared with carriers of all other alleles, OR = 3.2 (95% CI 1 8–5.8); (χ2 = 18.036 υ = 1 p < 0.0001), carriers of allele 2 (χ2 = 15.784 υ = 1 p < 0.0001), allele 3 (χ2 = 6.845 υ = 1 p < 0.01) and allele 4 (χ2 = 18.103 υ = 1 p < 0.0001). DRD4 genotype 4/4, the most widely represented in the male population, was most frequently found in the group with a moderate level of vital exhaustion (60.2%). Carriers of the second most common genotype in the population: 2/4 genotype were more often found in the group where there was no vital exhaustion (15.6%). Carriers of the 3/3 and 3/4 genotype were more frequently found in the group with a severe level of vital exhaustion (3.9% and 9.2%, respectively) than in the group with moderate vital exhaustion (1.8% and 4, 1%, respectively). Carriers of the 4/5 and 7/7 genotype are more likely to be found in the group with a severe level of vital exhaustion (2.6%, respectively) than in other groups. Carriers of the 2/6 genotype (3.1%) and 4/6 genotype (5.5%) were more frequently found in the group with no vital exhaustion. Carriers of the 4/7 genotype (2.7%) and 6/6 genotype (2.7%) were most often found in the group with moderate vital exhaustion (χ2 = 39.186 υ = 36 p > 0.05). Carriers of the 2/2 genotype were more likely to be found in the group with a moderate level of vital exhaustion (7.7%) than in the group with a severe level of vital exhaustion (1.3%) in comparison with: representatives of all other DRD4 genotypes (χ2 = 4.039 υ = 1 p < 0.05), carriers of the 2/4 genotype (χ2 =4.217 υ = 1 p < 0.05); 3/3 genotype (χ2 = 5.218 υ = 1 p < 0.05); 3/4 genotype (χ2 = 6.868 υ = 1 p < 0.01); 3/6 genotype (χ2 = 3951 υ = 1 p < 0,05); 4/5 genotype (χ2 = 7.843 υ = 1 p < 0.01); 7/7 genotype (χ2 = 7.843 υ = 1 p < 0.01). Furthermore, carriers of the 2/2 genotype were more frequently found in the group with no vital exhaustion (6.3%) than in the group with severe vital exhaustion, compared with carriers of the DRD4 genotype 3/3 (χ2 = 5306 υ = 1 p < 0.05).

The distribution of the other carriers of the DRD4 genotype does not exceed 1.3% (**Table 1**). The different picture can be seen in men with vital exhaustion in the carriage of long and short alleles of the DRD4 gene. Carriers of the DRD4 gene allele 2 are more frequently represented in the male group without vital exhaustion (16.4%) than in the group with a severe level of vital exhaustion (7.9%), moreover, in comparison with: carriers of all other DRD4 gene alleles (χ2 = 6.017 υ = 1 p < 0.01); carriers of allele 3 (χ2 = 8.830 υ = 1 p < 0.01); carriers of allele 4 (χ2 = 5.466 υ = 1 p < 0.01); allele 7 (χ2 = 5680 υ = 1 p < 0,01). Also, carriers of allele 2 were more often found in the group with a moderate level of vital exhaustion (14.7%) than in the group with a severe level (7.9%) as compared with carriers of

all other alleles (χ2 = 4.651 df = 1 p = 0.031); carriers of allele 3 (χ2 = 8.047 df = 1 p = 0.005); allele 4 (χ2 = 4.064 df = 1 p = 0.044). Carriers of the allele 3 are more frequently represented in the group with severe vital exhaustion (9.2%) than in the group where there was no vital exhaustion (4.3%) compared with carriers of all other alleles of the DRD4 gene OR = 2.26 (95% CI 0.9–5.1); (χ2 = 4.003 υ = 1 p < 0.05); carriers of the allele 6 OR = 4.83 (95% CI 1.3–17); (χ2 = 6.379 υ = 1 p < 0.01). Carriers of the allele 3 were also more often found in the group with moderate vital exhaustion (4.8%) than in the group with severe vital exhaustion (9.2%), compared with the carriers of all other alleles OR = 2 (95% CI1–4.1); (χ2 = 4.056 υ = 1 p < 0.05); carriers of the allele 6 OR = 3.6 (95% CI 1.1–11.5); (χ2 = 4.889 υ = 1 p < 0.05). Carriers of allele 7 were more frequently found in the group with severe vital exhaustion (3.3%) than in the group where there is no vital exhaustion (1.2%), compared with carriers of allele 6, which are more often represented in the group of men without vital exhaustion (7.4%) (χ2 = 4.848 υ = 1 p < 0.05). Carriers of the allele 4 of the DRD4 gene are represented at approximately the same frequency in all groups with and without vital exhaustion (68.8%, 70.8%, and 73.7%, respectively). Carrier of all other alleles of the DRD4 gene does not exceed 2% and is presented in **Table 1**. (χ2 = 20.495 υ = 12 p < 0.05).

We determined that the 10/10 homozygous genotype is found more frequently (54.8%), and the heterozygous 9/10 genotype is more rare - 36.6% in the frequency distribution of the VNTR genotypes of DAT gene polymorphism in the population among of men aged 25–64 years. 9/9 genotype was observed in 3.7%. The prevalence of the other genotypes was from 1.7% and lower. The similar situation in the population and in the carriage of alleles is 9–22% and 10–74.2%, which were more common than carriers of all other alleles (**Table 2**).

The distribution of carriers of VNTR genotypes of DAT gene polymorphism by the level of anxiety is presented in **Table 2**. Men, carriers of the 10/10 genotype in the group with moderate anxiety were found in 58.4%, and in the group with a severe level of anxiety - 50.6%, carriers of the heterozygous genotype 9/10 were respectively in the group with the moderate level of anxiety - 35% and in the group with a severe level of anxiety - 38.8% (χ2 = 51.105 υ = 16 p < 0.0001). Carriers of the 9/9 genotype were found much more frequently in the group with a severe level of anxiety (6.3%) than in the group with a moderate level of anxiety (1.6%), moreover, in comparison with representatives of all other genotypes, OR = 3.9 (95% CI 1.2–12.9); (χ2 = 6.098 υ = 1 p < 0.01), carriers of the 9/10 genotype OR = 3.4 (95% CI 1–11.1); (χ2 = 4.424 υ = 1, p < 0.05), and carriers of the 10/10 genotype OR = 4.3 (95% CI 1.3–14.4); (χ2 = 6.863 υ = 1, p < 0.01).

The distribution of carriers of VNTR genotypes of DAT gene polymorphism by the level of anxiety is presented in **Table 2**. Men, carriers of the 10/10 genotype in the group with moderate anxiety, were found in 58.4%, and in the group with severe anxiety - 50.6%, carriers of the heterozygous 9/10 genotype were respectively in the group with moderate anxiety - 35% and in the group with severe anxiety - 38.8% (χ2 = 51.105 υ = 16 p < 0.0001). Carriers of the 9/9 genotype were found much more frequently in the group with a severe level of anxiety (6.3%) than in the group with a moderate level of anxiety (1.6%), moreover, in comparison with representatives of all other genotypes, OR = 3.9 (95% CI 1.2–12.9); (χ2 = 6.098 υ = 1 p < 0.01), carriers of the 9/10 genotype OR = 3.4 (95% CI 1–11.1); (χ2 = 4.424 υ = 1, p < 0.05), and carriers of the 10/10 genotype OR = 4.3 (95% CI 1.3–14.4); (χ2 = 6.863 υ = 1, p < 0.01).

The distribution of carriers of VNTR genotypes of DAT gene polymorphism by depression level is presented in **Table 2**. Carriers of the 10/10 and 9/10 genotypes were found approximately equally in the group with depression (57.7%, 37.9%, respectively) and in the group without depression (56% and 36.1%, respectively)


**Table 2.** *Frequencies of VNTR genotypes and alleles of DAT gene polymorphism in a population and their association with psychosocial factors.*

*Association of Personal Anxiety with Dopamine Receptor D4 (DRD4), DAT Genes Polymorphism DOI: http://dx.doi.org/10.5772/intechopen.94386*

(χ2 = 13.549 υ = 8 p > 0.05). Carriers of the 9/9 genotype were more common in the group with depression (7.8%) than in the group without depression (2.1%), moreover, in comparison with representatives of all other genotypes, OR = 3.9 (95% CI 1.3–11.4); (χ2 = 7.583 υ = 1 p < 0.001) and carriers of the 10/10 genotype OR = 4 (95% CI 1.3–11.9); (χ2 = 7.477 υ = 1, p = 0.006). The ratio of the frequency of alleles 9 and 10 among men in groups with depression and without depression is similar to the distribution of these genotypes (χ2 = 9.235 υ = 5 p < 0.05) (**Table 2**). Carriers of allele 9 and allele 10 were found in the group with depression (26.7% and 70.7%, respectively) and in the group without depression (20.1% and 75.6%, respectively). Moreover, carriers of allele 9 were more frequently found in the group with depression than without it, in comparison with carriers of all other alleles OR = 1.4 (95% CI 1–2); (χ2 = 4.390 υ = 1, p < 0.05).

The distribution of carriers of VNTR genotypes of DAT gene polymorphism by level of vital exhaustion is presented in **Table 2**. Carriers of the DAT gene 9/10 and 10/10 genotypes were more common in the group where there was no vital exhaustion (38.3% and 57%, respectively); either in a group with a moderate level of vital exhaustion (37.1% and 55.4%, respectively); and in the group with a severe level, they were less common (31.8% and 48.5%, respectively) (χ2 = 41.076 υ = 16 p < 0.001). Men, carriers of the DAT gene 9/9 genotype, were significantly more likely to be found in the group with a severe level of vital exhaustion (15.2%) than in the group with a moderate level of vital exhaustion (2.3%) in comparison with carriers of other genotypes OR = 7.4 (95% CI 2.4–22.6); (χ2 = 16.238 υ = 1 p < 0.0001), carriers of the 9/10 genotype OR = 7.5 (95% CI 2.3–24.3); (χ2 = 13.815 υ = 1 p < 0.0001), carriers of the 10/10 genotype OR = 7.3 (95% CI 2.3–23.11); (χ2 = 14.769 df = 1 p = 0.0001). The ratio of the frequencies of alleles 9 and 10 of the DAT gene in men in different groups of vital exhaustion is similar to the distribution of these genotypes (χ2 = 19.792 υ = 10 p < 0.05). Carriers of allele 9 were more frequently found in the group with a severe level of vital exhaustion (31.1%) than in the group with a moderate level (20.9%), in comparison with carriers of all alleles of the DAT gene OR = 1.7 (95% CI 1, 1–2.6); (χ2 = 5.831 υ = 1 p < 0.01), carriers of the allele 10 OR = 1.7 (95% CI 1.1–2.6); (χ2 = 5.772 υ = 1 p < 0.01) and than in the group where there was no vital exhaustion (19.1%) in comparison with carriers of all alleles of the gene DAT OR = 1.9 (95% CI 1.1–3); (χ2 = 6.946 υ = 1 p < 0.01), carriers of the 10 allele of the OR gene = 1.9 (95% CI 1.1–3.1); (χ2 = 7.224 υ = 1 p < 0.01). In contrast, carriers of the 10 allele of the DAT gene, compared with carriers of all other alleles of the DAT gene, were more likely to have a moderate level of vital exhaustion (74.9%) (χ2 = 4.795 υ = 1 p < 0.05) or there was no vital exhaustion (77,7%) (χ2 = 7.072 υ = 1 p < 0.01), than a high level of vital exhaustion was observed (62.2%) (**Table 2**).

#### **8. Discussion**

In this study, we made an attempt to analyze the relationship between the DRD4 and DAT genes, since dopamine is involved in many cognitive and motivational processes; dopaminergic neurons are located in several parts in the midbrain; and dopaminergic axons extend to several regions of the striatum, hippocampus, tonsil, thalamus and cortex, and psychosocial factors, because the coordinated work of mediators and brain modulators underlies the emotional state and behavior of animals and humans [27].

The most frequent VNTR polymorphism of the DRD4 gene in the male population was the 4/4 homozygous genotype (57.9%), which is generally characteristic of Caucasoid populations. In second place we can see carriers of genotypes with short allele 2 of the DRD4 gene from 6 to 12% in frequency of occurrence in our

population. This allele is more characteristic of Central Asian populations [28]. The frequency of carriage of longer alleles 6 and higher of the DRD4 gene did not exceed 6% among the participants. In the world the variant with 7 repetitions of DRD4 (20.6%) is more frequently found, and more often we can see this genotype in the US population [28].

In this study, male carriers of the 4/6 genotype of the DRD4 gene were more likely to be found in the group with a severe level of anxiety and depression. We have established a certain trend among men with different levels of vital exhaustion: with an increase in the number of tandem turns of the VNTR of the DRD4 gene polymorphism, the level of vital exhaustion increased. Carriers of the DRD4 allele 6 were more common among men with depression. Severe levels of vital exhaustion were more common among carriers of the allele 7. According to modern concepts of dopamine biosynthesis, it is known to take part in the so-called adaptation process.

Lack of dopamine results in depletion of the nervous system, and its increased level causes bipolar disorders [4, 27]. It has been shown that in people with the long form of the DRD4 gene (the number of repeats is six or more), the affinity of dopamine for the receptor is reduced and the number of receptors is reduced. These individuals are less sensitive to dopamine. So, they need more stimulation than people with a short form of the gene to get the same reaction [29]. Probably this is the reason for the high frequency of occurrence of genotypes with long allele of the DRD4 gene in men with anxiety, depression, and vital exhaustion.

As in the case of the DRD4 gene, VNTR polymorphic variants of the DAT gene can be associated with some pathological conditions in the pathogenesis, which play the main role in dopamine metabolism disorders [30]. In the studied population, the homozygous 10/10 genotype of the DAT gene prevailed - more than 50%, less often the 9/10 genotype was found slightly more than 36%, and finally, the third place was occupied by the 9/9 genotype - 3.7%. The incidence of the other genotypes was below 1.7%. According to literature data, the most represented was the allele with 10 repeats (60% - 93%) in all studied populations. The frequency of the allele with 9 repeats, which is the second most common, varies from 4.2–39%. The other alleles are present in all populations with a frequency of less than 3% [31]. Carriers of VNTR polymorphism of the 9/9 genotype of the DAT gene were more common among men with a severe level of anxiety, depression, and vital exhaustion. Similarly, carriage of allele 9 increased the chance of falling into the groups mentioned above.

Although studies on the association between anxiety, depression, life exhaustion, and VNTR polymorphism in the dopamine transporter gene are not available in the world literature, it may be associated with some pathological conditions in a number of cases; in the pathogenesis of which disorders in the dopaminergic system of the brain play the main role. It is known that individuals having a short version of the DAT gene in the genome, often develop post-traumatic stress disorder [32], which to some extent explains the results.

In summary, we should note that the genetic features found in the open male population may be responsible for the pathophysiological changes in the functioning and compensatory abilities of the dopaminergic system and are a background predisposing to the development of psychological and social risk factors for cardiovascular diseases (arterial hypertension, myocardial infarction, stroke).

#### **9. Summary**

In the population among men aged 25–64 years, the 4/4 homozygous genotype of the dopamine receptor 4-subtype DRD4 gene (57.9%) is the most represented.

*Association of Personal Anxiety with Dopamine Receptor D4 (DRD4), DAT Genes Polymorphism DOI: http://dx.doi.org/10.5772/intechopen.94386*

2/2 genotype - 6.1%, 2/4 genotype - 12.5%, and 3/4 genotype - 5.6% are less frequently found; and more rarely - 4/6 genotype (4.2%), 2/6 genotype, 4/7 genotypes and 6/6 genotype were present in equal proportions of 2.1%.The frequency distribution of alleles showed that the 4 allele predominates - 70.7%, the 2 allele was found at 14%, the 6 allele was at 6%. The other alleles make up 0.8% - 5.4%.

We have found that the 10/10 homozygous genotype is more common (54.8%), and the heterozygous 9/10 genotype is more rare (36.6%) with the frequency distribution of the VNTR genotypes of the DAT gene polymorphism. The 9/9 genotype was observed in 3.7%. The prevalence of the other genotypes was from 1.7% and lower. The frequency distribution of alleles showed that the alleles were 9–22%, 10–74.2%, which were more common than carriers of all other alleles. The 4/6 genotype of the DRD4 gene is strongly associated with mild anxiety, depression. The 7 allele of the DRD4 gene is strongly associated with a severe level of vital exhaustion. The 9/9 genotype of the DAT gene is strongly associated with severe anxiety, depression, and vital exhaustion.

## **Acknowledgements**

The research was carried out under the state assignment within the framework of budget theme No. АААА-А17-117112850280-2.
